Is CYCS p.Ala97Thr (c.289G>A) pathogenic?

CYCS p.Ala97Thr (c.289G>A) is classified Uncertain significance in CYCS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely benign (0.1352); Very rare (popmax 6.89e-05%).

How common is CYCS p.Ala97Thr (c.289G>A) in the general population?

CYCS p.Ala97Thr (c.289G>A) is very rare (popmax 6.89e-05%) (gnomAD).

What do computational predictors say about CYCS p.Ala97Thr (c.289G>A)?

AlphaMissense predicts likely benign (score 0.1352) — an in-silico prediction, not a clinical call.

CYCS p.Ala97Thr

c.289G>A · VCV3655332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.89e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1352	likely benign
REVEL	0.667	pathogenic-leaning
SaProt	LLR -10.30	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 415 bp · p 0.00062 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.89e-05%

Overall 6.89e-05% 1/1,451,536 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CYCS
Protein: p.Ala97Thr
Coding: c.289G>A
MANE Select: NM_018947
Type: single nucleotide variant
Location: chr7:25123730 (GRCh38)
Gene constraint: LOEUF 0.335 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.95 · 13 PDB
Residue 97: an α-helix

Full CYCS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYCS p.Ala97Asp Likely pathogenic ★ same residue
CYCS p.Gly42Ser Likely pathogenic ★★ same type
CYCS p.Ala52Thr Uncertain significance ★★ ⚠ same type
CYCS p.Leu33Val Uncertain significance ★★ ⚠ same type
CYCS c.-6T>G Benign/Likely benign ★★ same type
CYCS p.Ala51= Likely benign ★★ same type
CYCS p.Ile59= Likely benign ★★ same type
CYCS p.Pro72= Likely benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cycs-p-ala97thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown